O-(2-aminoethyl)oximes of alkyl 2-(and 3-)benzofuranyl ketones

ABSTRACT

O-(2-AMINOETHYL) OXIME DERIVATIVES HAVING ANTIDEPRESSIVE ACTIVITIES.

United States Patent 3,658,850 O-(Z-AMINOETHYDOXIMES 0F ALKYL 2-(AND 3-) BENZOFURANYL KETONES Jenkin Eric Davies and Jan van Dijk, Houtenlaan, Weesp, Netherlands, assignors to U.S. Philips Corporation,

New York, N .Y.

No Drawing. Filed July 16, 1969, Ser. No. 842,334 Claims priority, application Netherlands, July 18, 1968, 6810333 Int. Cl. C07d 5/42 U.S. Cl. 260346.2 3 Claims ABSTRACT OF THE DISCLOSURE O-(Z-aminoethyl) oxime derivatives having antidepressive activities.

The invention relates to new compounds of the Formula and pharmaceutically acceptable acid addition salts thereof, in which Formula A and B together form a benzo group, in which case R'=H or CH R=H or an alkyl group containing from 1 to 5 carbon atoms, and X=O, NH or S, or A and B each represent a hydrogen atom, a methyl group or a halogen atom (Cl, Br or I), in which case X=S, R'=H, halogen (Cl, Br or J) or CH and R=H, an alkyl group containing from 1 to 5 carbon atoms, a cycloalkyl group containing from 3 to 6 carbon atoms, a phenyl, mor p-chlorophenyl, m-, p-dichlorophenyl, thienyl-2 or 5-chlorothienyl-2 group, whilst when A and B each represent a hydrogen atom and X is a sulphur atom R and R may also together represent an orthophenylene group or a trimethylene group, in which case R is bound at the position 2, or a thienylene-2,3 group, in which case R is bound at the position 3.

The compounds according to the invention have interesting pharmacological properties. More especially they have a potent central activity, which may show itself both as an antidepressive activity, which may be due to monoamino oxidase inhibition, and as a sedative or anticonvulsive activity.

Especially the tricyclic compounds of the Formula I are very active and furthermore the derivatives of Z-acetyl- S-methylbenzfuran, of 3-acetyl-2-methyl benzthiophene, of

3-acetylindole, of 2chloro-5-acetyl-thiophene, of S-methyl-2-acetylthiophene and of the dithiophene have a strong activity.

The monoamino oxidase inhibiting activity of compounds of the Formula I was found in tests in which an amount of the test compound was intraperitoneally or orally administered to 5 male albino mice. After one hour the animals were subcutaneously injected with tryptamine hydrochloride in an amount of 250 mgs./kg. This amount caused no mortality in animals which had not received the test compound but did cause it in the treated animals. Eighteen hours after the administration of tryptamine hydrochloride the number of dead treated animals was determined. From the results the ED was determined.

The antidepressive activity of compounds according to the Formula I was determined in the tetrabenazine test. An amount of the test compound was intraperitoneally or orally administered to 5 male albino mice. After 45 minutes the animals were subcutaneously injected with 80 mgs./kg. of tetrabenazine. After another 45 minutes the degree of ptosis was determined and compared with the 3,658,850 Patented Apr. 25, 1972 ptosis of animals which had received tetrabenazine only. From the results the ED was determined.

The sedative activity of compounds according to the invention was found in the hexobarbital sleeping test. In this test a test compound was administered intraperitonally or orally 30 minutes or 60 minutes respectively before the administration of a just not narcotic dose of hexobarbital (30 mg./ kg. intravenously). Induction of the narcosis was the criterium for the activity of the substance. From a series of tests in which different doses were used the ED was calculated.

The anticonvulsive activity of compounds according to the invention against supra maximal electroshock was determined in female mice either 30 minutes after intraperitoneal administration or 60 minutes after oral administration of the test compound.

The influence of compounds on the convulsive activity of a supramaximal intraveneously administered dose of pentamethylene tetrazole (50 mgs./kg.) was also determined in female mice either 30 minutes after intraperitoneal or 60 minutes after oral administration of a compound.

The antidepressive compounds according to the invention are particularly suitable for use in the therapy of neurotic and psychotic disorders, especially the depressive syndrome, and also for the treatment of psychosomatic disorders. Therefore the substances may be administered to depressive patients as a psycho-stimulant.

The sedative compounds are highly suitable for use as ataraxics. They may successfully be used for the treatment of mild psychoneurotic phenomena.

The anticonvulsive compounds may be used in the treatment of epileptic patients.

The compounds may be administered in the usual manners after having been converted to a form suitable for administration. They may be injected or they may be administered orally or rectally. Hence suitable forms of administration are: injection liquids, pills, tablets, drages, capsules, powders and the like.

The manner in which, the amount in which and the frequency at which the substances have to be administered to the patient may differ from patient to patient and also in accordance with the seriousness of the disorders. Generally the doctor treating a patient will have no trouble in choosing the correct therapy for him or her.

The daily dose of sedative and antidepressive compounds Will generally be from 10 to 500 mgs. for adults. As a rule an amount of 10 to 5'0 mgs. will be suflicient.

Anticonvulsives according to the invention will generally be administered in a daily dose of to 500 mgs.

The compounds in accordance with the invention can be converted into preparations by methods commonly used in pharmacy, for example by mixing an active substance with, or dissolving it in, solid or liquid carrier materials.

As such the usual carriers may be employed, for example water, which, if desired, may be made isotonic with blood, glycerine, chalk, calcium phosphate, lactose, powdered sugar or calcium carbonate. As swelling agents in tablets and drages use may be made of, for example, potato starch, mais starch, arrowroot (amylum marantae), carboxymethyl cellulose, gelatine and acaciagum.

Suitable lubricants are talc, magnesium stearate, calcium stearate and stearic acid. Preparations to be orally administered may include flavouring substances, such as sugars or vanilla extracts.

As preservatives propyl-p-hydroxybenzoate and benzyl alcohol may be used. The preparations may further contain surface-active substances, such as mono-, diand triesters of higher fatty acids.

Examples of acids with which the compounds can form pharmaceutically acceptable acid addition salts are halogen hydracids, such as hydrochloric acid and hydrobroinic acid, furthermore other inorganic acids, such as sulphuric acid, nitric acid and phosphoric acid, and organic acids, such as citric acid, acetic acid, oxalic acid, fumaric acid, lactic acid, succinic acid, sulphamic acid, benzoic acid, tartaric acid, gallic acid, malic acid and maleic acid.

The compounds according to the invention may be produced by known methods.

The invention relates also to a method of producing new oxime ethers which is characterized in that compounds of due Formula I and pharmaceutically acceptable acid addition salts thereof, in which formula A and B together form a benzo group, in which case R'=H or CH R=H or an alkyl containing from 1 to carbon atoms and X=O, NH or S, or A and B each represent a hydrogen atom, a methyl group or a halogen atom (Cl, Br or I), in which case X=S, R'=H, a halogen (Cl, Br or I) or CH and R=H, an alkyl containing from 1 to 5 carbon atoms, a cycloalkyl containing from 3 to 6 carbon atoms, a phenyl, mor p-chlorophenyl, m, p-dichlorophenyl, thienyl-Z or S-chlorothienyl-Z group, while, when A and B each represent a hydrogen atom and X represents a sulphur atom, R and R may also together represent an orthophenylene group or a trimethylene group, in which case R is bound at the 2-position, or a thienylene-2,3 group in which case R is bound at the 3-position.

Thus compounds according to the invention may be produced by reacting a compound of the Formula II where M represents a hydrogen atom or an alkali metal atom, with a compound of the Formula HI Y III or a salt thereof, where Z represents a halogen atom, preferably a bromine or chlorine atom, or a tosyloxy group and Y represents a hydrogen atom or an acyl group whilst when Y represents an acyl group this acyl group is split off by hydrolysis after the coupling reaction. The acyl group may be the ethoxycarbonyl group or the carbobenzoxy group.

The reaction can be performed in a suitable solvent. Some of the suitable solvents are: alcohols, such as methanol, ketones, such acetone and M.E.K., and ethers, such as dioxan and dimethylglycol ether. Splitting off of an acyl Y may be effected with, for example, KOH in an alcohol, for example ethanol.

When in Formula II M represents a hydrogen atom, an acid binder is preferably added to the reaction mixture. Suitable acid binders are inter alia alcoholates, potassium carbonate, sodium carbonate, tertiary amines, pyridine and the like.

The temperature of the reaction mixture may vary within comparatively wide limits. Generally, however, it will be between 0 C. and 50 C.

The oximes of the Formula 11 may be obtained in the usual manners from the corresponding aldehydes or ketones with the aid of hydroxylamine. The oximates can be produced from the oximes by adding the latter, as the case may be dissolved in alcohol, to a solution of sodium or potassium alcoholate or sodium or potassium hydroxide in alcohols.

The acylated amines of the Formula III can be produced by starting from the corresponding primary or secondary amine and an acid chloride dissolved in, for example, benzene.

Compounds according to the invention may also be obtained by reacting a compound of the Formula IV in which formula the substituents have the same meanings as in Formula I, with a compound of the Formula V The reaction is preferably carried out in a solvent at room temperature. Suitable solvents are inter alia: alcohols, pyridine, dioxane, dimethylformamide, tetrahydrofuran and the like.

The compounds of the Formula I may also be obtained by reacting a compound of the Formula VI with ammonia.

In the Formula VI, Z represents a halogen atom, preferably a bromine atom, or a tosyloxy group. The reaction may be carried out in, for example, alcohols.

The starting substances of the Formula VI may be obtained by reacting oximes of the Formula II (M=H) in the presence of an acid binder with a halogen compound of the Formula VII where Z has the same meaning as in Formula VI and Hal represents a halogen atom, preferably a bromine atom.

EXAMPLES (1) O (2 aminoethyl)-2-acetylbenzofuranoxime- HCl.8.75 g. of Z-acetylbenzofuran oxime, than 20.5 g. of hydrobromide of 2-bromoethylamine were added whilst stirring to a solution of 4.60 g. of sodium in mls. of absolute ethanol. The mixture was stirred at room temperature for 2 /2 hours, after which the produced precipitated sodium bromide was drawn off. The filtrate was evaporated in vacuo until the solvent had largely been removed, after which the residue was mixed with about 50 mls. of water and S0 mls. of ether. The mixture was mixture was agitated, after which the layers produced were separated, the ethereal solution was washed twice with about 30 mls. of water and then extracted with 50 mls. of 2 N hydrochloric acid. The acid extract was rendered alkaline by means of 75 mls. of 2 N sodium hydroxide and then extracted thrice with 50 mls. of ether. The resulting etheral solution was washed thrice with 30 mls. of water and then dried over sodium sulphate. After the ether had been removed in vacuo the basic residue was neutralised with 2 N alcoholic hydrochloric acid. After this solution had been diluted with absolute diethyl ether the above-mentioned substance crystallised out. After it had been recrystallised from a mixture of ethanol and diethyl ether the substance had a melting range between 199.S C. and 20l.5 C.

(2) 0 (2 aminoethyl)-3-acetylindole oxime-HCl.-- 8.70 g. of 3-acetylindole oxime were added whilst stirring to a solution of 4.60 g. of sodium in mls. of absolute ethanol. After the oxime had been dissolved, 20.5 g. of

layer was then extracted with 50 mls. of 2 N hydrochloric acid. This hydrochloric acid extract was mixed with 75 mls. of 2 N sodium hydroxide and subsequently extracted trice with 50 mls. of ether. This ethereal solution was washed thrice with 30 mls. of water, then dried over sodium'sulphate'and subsequently evaporated in vacuo. The resulting residue was neutralised with 2 N ethanolic hydrochloric acid, after which the above-mentioned. substance crystallised slowly after the addition of a small amount of ether. The substance was drawn off and recrystallised from a mixture of ethanol and ether. Melting point 174 C.-l77 C.

(3) O (2 aminoethyl) 8-H-indeno [2,l b] thiophene-8-ene oxime-HCl.A mixture of 5.56 g. of 8-H- indeno [2,'1-'b] thiophene-8-one, 4.91 g. of dihydro'chloride of O-(2-aminoethyl)hydroxylamine and 2.71 g. of sodium acetate was stirred at room temperature with 175 mls. of ethanol and 20 mls. of water for 1 /2 hours. The solid substance gradually dissolved in the solvent. The reaction mixture was allowed to stand for 18 hours and then evaporated in vacuo at a temperature of about 40 C. The residue was mixed with 150 mls. of water and the mixture wasextracted with altogether 175 mls. of diethyl ether. The aqueous solutions was then rendered basic with 30 mls. of 2 N potassium hydroxide and subsequently extracted with altogether 200 mls., of diethyl ether. The latter extract was washed with-water and' dried over sodium sulphate. The residue obtained after thesolvent hadbeen distilled off in vacuo was dissolved in 15 mls. of absolute ethanol and then neutralised with 2 N ethanolic hydrochloric acid. After the addition of a small amount of ether to the neutralized solution the above-mentioned substance'crystallised out which'has a melting point of 188 C. with decomposition.

(4) O (2 aminoethyl) 2 acetyl-S-methylthiopheneoxime-HClr-A solution of 1.40 g. of 2-acetyl-5- methylthiophene and 1.49 g." of O-(2-aminoethyl) hy-.

droxylamine dihydrochloride in a mixture of 5 mls. of dry pyridine andmls. of absolute ethanol was refluxed for 3 /2 hours. The solvents were then distilled off in drochloride of the above-mentioned substance crystallised out. By heating the mixture and adding 10 mls. of ethanol the hydrochloride was dissolved again. By mixing this solution with 10 mls. of absolute ether the hydrochloride crystallised out again. The mixture was allowed to stand overnight in a refrigerator and subsequently mixed with 40 mls. of absolute ether. The substance which crystallised out was drawn off, washed thrice with absolute ether and dried; melting point 189 C.-191 C.

(5a) 0 (2 aminoethyl) 2 hexanoylthiopheneoxime-HCl.-19.7 g. of 2-hexanoylthiopheneoxime were dissolved in a solution of 4.6 g. of sodium in 100 mls. of absolute ethanol. The resulting solution was added whilst stirring at 20 C. to a mixture of mls. of 1,2-dibromoethane at 50 mls. of N,N-dimethylformamide. The reaction mixture was then heated to C. and maintained at this temperature for 16 hours. The precipitate which formed was drawn off and the filtrate was concentrated in vacuo. After the addition of 200 mls. of water the concentrate was twice extracted with mls. of chloroform. The extract was dried over sodium sulphate, concentrated in vacuo and then distilled in a high vacuum (0. 005 mm). The distillate contains, in addition to 2- hexanoylthiopheneoxime, the O (2-bromoethyl)-2-hexanoylthiopheneoxime.

(5b).--A solution of 5 g. of this distillate in 50 mls. of ethanol was mixed with 50 mls. of concentrated ammonia. This mixture was then stirred in a closed vessel at 65 C. for 16 hours and subsequently concentrated in vacuo. The concentrate was mixed with 50 mls. of ether and then extracted thrice with 20 mls. of N hydrochloric acid. The acid extract was washed with 50 mls. of ether, then rendered basic with 40 mls. of 2 N sodium hydroxide and again extracted thrice with 30 mls. of ether. This ethereal extract was dried over sodium sulphate, concentrated and the residual oil distilled in a high vacuum. The distillate, was absorbed in diethyl ether and neutralized with 2 N ethanolic hydrochloric acid with the result that the hydrochloride of O-(Z-aminoethyl)-2-hexanoylthiopheneoxime crystallised out. Melting range 100-110 C.

(6).The following table relates to a number of substances according to the invention prepared by methods A, B or-C and states their melting points and pharmacological properties. Ihe method A consisted in a reaction of a compound of the Formula II with a compound of the Formula "III; themethod -B consisted in a reaction of a compound of the Formula IV with a compound of the Formula V;- the method C consisted in a reaction 05E a compound of the Formula V1 with ammonia. By these methods the following substances were obtained.

TABLE Melting Point of Anti- Anti- H01 salt Sedacondepres- Substance Method 1n0 tlve vulslve sant B- Ls -(i3=NO0H1CHr-NH:

H H A -16 -F 01 OH; A 228.5230.5 CH CH B 189-191 H cyclfipropyl A 112-115 H 11.05 11 C 100-110 H CflHu A 146-150 H Thienyl-2 A 192-194 5-chl0rth1enyl-2 A 116-116 See footnotes at end of table.

v I TABLEg-Con-timued Melting r Point of ,Antiv Anti- HCl salt Sed-a- 'condepres- Substance Method in C, tive v vulsive san't:

IRIOCHI CHTNHI A 209-211 p B z 188 /VO II0.-CH1-CH1NH1; I B 205f x/Jgl I r 1 I-'0CH3CH;NH:

I I V S C=N--'CHz-CH NH 174-177 (a) (a) (a).

Maleate. Dmomposltion. Base, oil.

NorE:

-=Not active or scarely active. +=Active.

' Tablet R 0-(Z-aminoethyl)-2-acetylbenzofuranoxime-HCl 50 'T HT lactose l 335 Potato starch 60 Talc 25 Magnesium stearate t 5 Gelatine .i 5

Suppository Mg. O-(a aminoethyl)acetylindoleoxime-HCI ;J Suppository material 1500 Injection liquid 7 fi G. O (2 aminoethyl) 8H-indene{2,1-b] thiophene-S- H one-oximne-HCI l 25 Methyl-p.hydroxybenzoate 1.80 Propyl-phydroxybenzoate 0.20 Sodium chloride Polysorbate 80 U.S.P. 4.0

Water up to 1000 mls.

consisting of R v A 0,. wherein'R' is a moiety selected from the group consisting 0 of hydrogen and methyl and R is a moiety selected from the group consisting of hydrogen and alkyl of 1 to 5 carbon atoms and the salts thereof with pharmaceutically acceptable acids.

-2.--A compound of claim 1 wherein R and R are each hydrogen.

3. As a compound of claim 1, O-(Z-aminoethyD-Z- acetyl benzofuranoxime and the salts therof with pharmaceutically acceptable acids.

References Cited UNITED STATES PATENTS 3,513,239 5/1970 Willey 260346.2 r.

ALEX MAZ-EL, Primary Examiner B. I. DENTZ, Assistant Examiner US. Cl. X.R.

22 3 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 658,850 LPHN 3358) Dated April 25. 1972 Inventor(s) JEN'KIN ERIC DAVIES ET AL It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

T- Column 1, line 9, "6,810, 333" should read 6,810, 133

Signed and sealed this day of 1972.

Signed and sealed this 17th day of October 1972.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTISCHALK Attesting Officer Commissioner of Patents 

